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组蛋白去乙酰化酶(histone deacetylases,HDACs)抑制剂可以在转录水平上调控基因表达,导致肿瘤细胞生长停滞,诱导肿瘤细胞分化和凋亡。目前应用最为广泛的氧肟酸结构可以与活性口袋底部锌离子螯合从而竞争性地抑制HDACs的去乙酰化作用,但是氧肟酸结构存在代谢不稳定和选择性差的缺点难以成药。本文以二酮酸酯结构作为潜在的锌离子结合基团对氧肟酸进行替代,共合成了8个目标化合物,并对其HDACs抑制活性和对多种肿瘤细胞株的抗增殖活性进行了研究。其中化合物CPUYS707对人髓系白血病细胞株U937的抗增殖活性GI50达到0.31μmol.L-1,优于阳性对照药物SAHA和MS-275。
Histone deacetylases (HDACs) inhibitors can regulate gene expression at the transcriptional level, leading to the arrest of tumor cell growth, inducing tumor cell differentiation and apoptosis. Currently, the most widely used hydroxamic acid structure can chelate the zinc ions at the bottom of the active pocket to competitively inhibit the deacetylation of HDACs. However, the hydroxamic acid structure has the disadvantages of unstable metabolism and poor selectivity. In this paper, 8 target compounds were synthesized by substituting the diketoate structure as a potential zinc ion binding group for hydroxamic acid, and their HDACs inhibitory activity and anti-proliferative activity against various tumor cell lines were studied . The anti-proliferative activity GI50 of the compound CPUYS707 to human myeloid leukemia cell line U937 was 0.31μmol.L-1, which was better than the positive control drugs SAHA and MS-275.